Inhibitory effects of NO on carotid body: contribution of neural and endothelial nitric oxide synthase isoforms

Abstract

Valdé s, Viviana, Matías Mosqueira, Sergio Rey, Rodrigo Del Rio, and Rodrigo Iturriaga. Inhibitory effects of NO on carotid body: contribution of neural and endothelial nitric oxide synthase isoforms. Am J Physiol Lung Cell Mol Physiol 284: L57-L68, 2003. First published September 6, 2002 10.1152/ajplung.00494.2001.-We tested the hypothesis that nitric oxide (NO) produced within the carotid body is a tonic inhibitor of chemoreception and determined the contribution of neuronal and endothelial nitric oxide synthase (eNOS) isoforms to the inhibitory NO effect. Accordingly, we studied the effect of NO generated from S-nitroso-Nacetylpenicillamide (SNAP) and compared the effects of the nonselective inhibitor N -nitro-L-arginine methyl ester (L-NAME) and the selective nNOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole (TRIM) on chemosensory dose-response curves induced by nicotine and NaCN and responses to hypoxia (PO2 Ϸ 30 Torr). CBs excised from pentobarbitoneanesthetized cats were perfused in vitro with Tyrode at 38°C and pH 7.40, and chemosensory discharges were recorded from the carotid sinus nerve. SNAP (100 M) reduced the responses to nicotine and NaCN. L-NAME (1 mM) enhanced the responses to nicotine and NaCN by increasing their duration, but TRIM (100 M) only enhanced the responses to high doses of NaCN. The amplitude of the response to hypoxia was enhanced by L-NAME but not by TRIM. Our results suggest that both isoforms contribute to the NO action, but eNOS being the main source for NO in the cat CB and exerting a tonic effect upon chemoreceptor activity. chemoreceptor; nitric oxide THE VENTILATORY EFFECTS of nitric oxide (NO) and the role played by nitric oxide synthase (NOS) isoforms are complex (14,18,30). In the nucleus tractus solitarii, NO plays a significant excitatory role in sustaining the ventilatory response to hypoxia (14,18,35). However, several lines of evidence indicate that NO produced within the carotid body (CB) is an inhibitory modulator of hypoxic chemoreception (2,8,20,25,34,38). The administration of the precursor L-arginine, NO donor molecules (8,22,38), and NO gas (20) to the cat CB perfused in vitro reduces the chemosensory response to hypoxia. On the other hand, the inhibition of NOS increases the frequency of carotid chemosensory discharges (f x ) in the cat CB in situ and in vitro (19,38). However, little is known about the effects of NO on chemosensory responses induced by other excitatory stimuli, such as nicotine and NaCN. In a previous paper, we found that the NO donor sodium nitroprusside (SNP) reversibly reduced chemosensory responses induced by single doses of NaCN and nicotine in the superfused cat CB (2). In anesthetized cats, the NOS inhibitor N -nitro-L-arginine methyl ester (L-NAME) increased basal f x and enhanced responses to NaCN and dopamine (19). These results suggest that, besides the well-known inhibitory effect of NO on hypoxic chemoreception, NO may also modulate the responses to other stimuli.In the cat CB, NOS immunoreactivity and diaphorase activitie...

Carotid body function in heart failure

“…Existing evidence of the role of eNOS vs nNOS in the CB is somewhat controversial. Studies have shown that a nonspecific NOS inhibitor,N G -nitro-L-arginine methyl ester (L-NAME), significantly enhances the CB ventilatory response in rats (Haxhiu et al 1995) and cats (Valdés et al 2003); but specific nNOS inhibitors were ineffective. On the other hand, using mutant mice deficient in nNOS and eNOS isoforms, (Kline et al 1998) found that mice lacking nNOS showed greater ventilatory responses to hypoxia than wild-type controls; whereas responses to hypoxia were blunted in mutant mice lacking eNOS compared with the wild-type.…”

Gene Transfer of Neuronal Nitric Oxide Synthase to Carotid Body Reverses Enhanced Chemoreceptor Function in Heart Failure Rabbits

“…Several studies have shown that a nonspecific NOS inhibitor, L-NAME, significantly enhances the ventilatory response to NaCN in rats 3 and CB response to hypoxia in cats; 23 but specific nNOS inhibitors were ineffective on them. 3,23 Conversely, using mutant mice deficient in nNOS and eNOS isoforms, Kline et al 24,25 found that mice lacking nNOS showed greater ventilatory responses to hypoxia than wild-type controls; whereas responses to hypoxia were blunted in mutant mice lacking eNOS compared with the wild-type.Our study confirms previous studies showing the presence of nNOS in nerve fibers in the CB. 5,22 Furthermore, our results demonstrate that nNOS protein expression and NO production are markedly lower in the CB from CHF rabbits compared with that in sham rabbits.…”

“…Two studies concluded that a nonspecific NOS inhibitor, L-NAME, significantly enhanced the ventilatory response to NaCN in rat 3 and the CB chemoreceptor response to hypoxia in cats; 23 whereas specific nNOS inhibitors were ineffective. 3,23 Conversely, Kline et al, 24,25 using mutant mice deficient in nNOS and eNOS isoforms, found that mice lacking nNOS showed greater ventilatory responses to hypoxia than wild-type controls; whereas responses to hypoxia were blunted in mutant mice lacking eNOS compared with the wild-type. Until now, even less is known about which isoform of NOS contributes to the enhanced peripheral chemoreceptor activity in CHF rabbits.…”

Increased Endogenous Nitric Oxide Release by Iron Chelation and Purinergic Activation in the Rat Carotid Body

“…Studies have shown the expression of purinoceptor subunits P2X2 and P2X3 in the nerve fibers co-localized with the glomus clusters [15,31]. In addition, NOS is localized in the nerve endings and plexus of nerve fibers in lobules of parenchyma cells and near small blood vessels of the carotid body, which plays physiological role in the NO inhibition of carotid chemoreceptor activity [25,26,32,33].…”